Process for producing acetylene compound

ABSTRACT

There is provided a process for producing an acetylene compound useful as an intermediate of pharmaceuticals, from 4-nitrofluorobenzene, in industrially and economically advantageous manner. Concretely, it is a method for producing an acetylene compound of formula (3)  
                 
 
characterized by reacting 4-nitrofluorobenzene of formula (1)  
                 
 
with an alkoxide of 2-methyl-3-butyn-2-ol of formula (2)  
                 
at −20 to 10° C.

TECHNICAL FIELD

The present invention relates to a process for producing an acetylenecompound from 4-nitrofluorobenzene and 2-methyl-3-butyn-2-ol. Thiscompound is useful as an intermediate for synthesizing e. g. ,antifibrillatory agents (see, JP-A-2001-151767) or hypotensive agents(see, J. Med. Chem. , 1983, Vol. 26, No. 11, 1582-1589).

BACKGROUND ART

As the prior method for producing an acetylene compound of formula (3),there is known a method in which 4-nitrophenol (compound (5)) is reactedwith 2-methyl-3-butyn-2-chloride (compound (6)) in the presence of abase (see, for example J. Med. Chem. , 1983, vol. 26, No. 11, p. 1582and JP-A-58-188880).

It is also reported a method in which 4-nitrophenol (compound (5)) isreacted with 2-methyl-3-butyn-2-chloride (compound (6), in the presenceof copper iodide catalyst, potassium iodide and potassium carbonate(see, for example Synthesis, 1995, vol. 6, p. 707).

Also, it is reported a method in which 4-nitrophenol (compound (5)) isreacted with a derivative of 2-methyl-3-butyn-2-ol (compound (7)) in thepresence of copper catalyst and DBU (1,8-diazabicyclo[5. 4.0]undec-7-ene) (see, for example Tetrahedron Lett. , 1994, vol. 35, p.6405).

In addition, it is reported a method in which 4-nitrophenol (compound(5)) is reacted with 2-methyl-3-butyn-2-ol in the presence oftriphenylphosphine and DEAD (diethyl azodicarboxylate) (MitsunobuReaction, see, for example Synth. Commun. , 1989, vol. 19, p. 1255).

As the preparing method by using 4-nitrofluorobenzene as a raw material,there is known a method in which 2-methyl-3-butyn-2-ol is used insteadof a solvent, and the raw material is reacted with potassium alkoxide of2-methyl-3-butyn-2-ol (see, for example J. Org. Chem. , 1972, vol. 37,p. 841).

(wherein X means Cl, —OCO₂CH₃ or —OCOCF₃. )

The preparing method described in J. Med. Chem. , 1983, vol. 26, No. 11,p. 1582, and JP-A-58-188880 has some problems, such as a low yield, theuse of 2-methyl-3-butyn-2-chloride (compound (6)) being relativelyunstable.

Although the preparing method described in Synthesis, 1995, vol. 6, p.707 gives an improved yield of 89% by using copper catalyst, it has someproblems, such as removal of the copper catalyst being heavy metal, andthe use of a large amount of potassium iodide that is not necessarilysaid to be inexpensive in case where potassium iodide is used, and thelike. In addition, a problem regarding the stability of2-methyl-3-butyn-2-chloride remains. Further, there is problems in theaspects of procedure ability and cost, such as the use of2-methyl-3-butyn-2-chloride in an amount of 2 times molar of4-nitrophenol (compound (5)).

The preparing method described in Tetrahedron Lett. , 1994, vol. 35, p.6405 is similar to the above-mentioned method, but the yield is 81 % atmost in case where 2-methyl-3-butyn-2-chloride is used, the use oftrifluoroacetate that gives the highest yield (88%) is clearlydisadvantageous in the aspect of cost, and DBU used is also expensive.Therefore, this method is not suitable as an industrial preparingmethod.

Also, the preparing method described in Synth. Commun, 1989, vol. 19, p.1255 is not suitable as an industrial preparing method from viewpoint oflow yield (45%) and the cost of expensive DEAD or the like.

The preparing method described in J. Org. Chem. , 1972, vol. 37, p. 841can be said to be a preparing method excellent in the cost and procedureability as it use 2-methyl-3-butyn-2-ol and 4-nitrofluorobenzene as rawmaterials that are relatively inexpensive and stable, and it does notuse catalysts such as heavy metal. However, this method has problemssuch as low yield of 35%, long reaction time (room temperature, 3 days)or the like.

DISCLOSURE OF THE INVENTION

In order to dissolve the above-mentioned problems, the present inventorseagerly investigated reaction condition between 4-nitrofluorobenzene andan alkoxide of 2-methyl-3-butyn-2-ol. As a result of it, they found apreparing method, which is excellent in procedure ability and providesintended compounds in a good yield, and they consequently completed thepresent invention.

That is, the present invention relates to a method for producing anacetylene compound of formula (3)

characterized by reacting 4-nitrofluorobenzene of formula (1)

with an alkoxide of 2-methyl-3-butyn-2-ol of formula (2)

at −20 to 10° C.

In addition, it is found that the method according to the presentinvention can inhibit the production of by-product (compound (4)) thatcannot be easily removed in the subsequent steps.

BEST MODE FOR CARRYING OUT THE INVENTION

The process for producing the acetylene compound of formula (3) will beexplained.

The acetylene compound of formula (3) can be produced in a good yield byreacting an alkoxide of 2-methyl-3-butyn-2-ol of formula (2) with4-nitrofluorobenzene of formula (1) in a solvent at −20 to 10° C.

As the alkoxide of 2-methyl-3-butyn-2-ol of formula (2) used in thepresent invention, metal alkoxides are generally used, and as the metalof the metal alkoxide, alkali metal such as sodium, potassium or lithiumor the like is preferable, and sodium is more preferable from viewpointof ease of handling and reactivity.

The used amount of the alkoxide of 2-methyl-3-butyn-2-ol of formula (2)is 0. 5 to 20 times moles based on the used amount of4-nitrofluorobenzene of formula (1). In the meantime, as the yield islowered in the used amount of 1 time mole or less, the amount of 1 timemole or more is preferable, and the amount of 1 to 3 times moles is morepreferable from viewpoint of cost.

As the procedure process of the reaction, it is preferable to adddropwise 4-nitrofluorobenzene of formula (1) to a solution composed of asolvent and the alkoxide of 2-methyl-3-butyn-2-ol of formula (2).

The time required for the dropwise addition is preferably 0. 5 to 5hours although it is not limited so long as a rapid rise in temperaturein the reaction system does not occur and a set temperature ismaintained.

The solvents used in the present invention include amide type solventssuch as N,N-dimethylacetamide, N,N-dimethylformamide,N-methylpyrrolidone, N,N′-dimethylimidazolidinone or the like, aromatichydrocarbon type solvents such as toluene, xylene or the like, aliphatichydrocarbon type solvents such as hexane, heptane or the like, andhalogen containing hydrocarbon type solvents such as dichloromethane,chloroform or the like, and mixed solvents of plural solvents mentionedabove.

Preferable solvents include amide type solvents, more preferablyN,N-dimethylacetamide and N,N′-dimethylimidazilidinone, from viewpointof the yield of the acetylene compounds of formula (3).

Used amount of the solvent is preferably 2 mass times or more that of4-nitrofluorobenzene of formula (1), and more preferably, for example 2to 4 mass times or for example 2 to 3 mass times from viewpoint of cost.

Although the reaction temperature ranges from −20° C. to 10° C. , it ispreferably a range of −10 to 0° C. from viewpoint of the elongation ofreaction time due to lowering of reaction temperature and the inhibitionof production of by-product of formula (4).

As the reaction time and reaction temperature cannot be specified ingeneral as they depend on the used amount of the alkoxide or the like.

The acetylene compound of formula (3) being a product can be obtained asa crude product by adding water, then extracting with an organic solventsuch as toluene, and washing and then distilling out the solvent.

The crude product can be used as such for the production of a benzopyranintermediate, and it can be purified by column chromatography ordistillation, etc. , if necessary.

The alkoxide of 2-methyl-3-butyn-2-ol of formula (2) being a rawmaterial in the present invention can be generally produced byprocessing 2-methyl-3-butyn-2-ol of formula (2) with a metal hydridesuch as sodium hydride, potassium hydride or the like, or with a metalsuch as metal sodium, metal potassium, metal lithium, or the like.

The acetylene compound of formula (3) produced according to the presentinvention is led to a benzopyran derivative that is an intermediate forsynthesizing an antifibrillatory agent or a hypotensive agent, by apreparation method shown in the following reaction scheme.

That is, the acetylene compound of formula (3) can be converted to anintermediate for synthesizing the above-mentioned antifibrillatory agentor hypotensive agent, by cyclizing it under heating to lead a benzopyrancompound, and reducing and acetylating the resulting compound.

The by-product of formula (4) formed in the production of the acetylenecompound of formula (3) cannot be perfectly removed even bycrystallization of the above-mentioned acetylamino form. Therefore, itis important for improvement in efficiency of the subsequent preparationto inhibit the formation of the by-product of formula (4) in theproduction of the acetylene compound of formula (3).

Hereinafter, the present invention is concretely described according toexamples to which the present invention is not limited.

In the meantime, HPLC relative area percentage was measured under thefollowing analytical condition:

-   Column: L-Column ODS φ44. 6 ×250 mm (manufactured by Chemicals    Evaluation Research Institute, Japan);-   Elution solution:    -   0 to 45 min CH₃CN-0.01 M AcONH₄ (45/55 v/v)    -   45 to 65 min CH₃CN-0.01 M AcONH₄ (45/55 v/v→95/5 v/v)    -   65 to 85 min CH₃CN-0.01 M AcONH₄ (95/5 v/v);-   Detection: UV (254 nm);-   Flow rate: 1 mL/min. ;-   Column temperature: 40° C.

EXAMPLE 1

To a 300 mL-reaction flask equipped with a thermometer, a stirrer and adropping funnel, 96. 0 g of N,N-dimethylacetamide (DMAC) and 11. 6 g(290 mmol) of 60% sodium hydride (suspension in mineral oil) were added,and 25. 2 g (300 mmol) of 2-methyl-3-butyn-2-ol was added dropwise withstirring under cooling with ice to produce an alkoxide (dropwiseaddition time: 2 hours).

After stirring for 30 minutes, 33. 8 g (240 mmol) of4-nitrofluorobenzene was added dropwise (under cooling with ice,dropwise addition time: 1. 5 hour), and after completion of dropwiseaddition the resulting mixture was stirred at the same temperature for18 hours. To the reaction mixture, 480 mL of water and 480 mL of toluenewere added and the resulting mixture was shaken. After allowing tostand, the mixture was separated into two-phase and the toluene phasewas taken out. The aqueous phase was extracted with 240 mL of tolueneagain and the resulting toluene phase was combined with the toluenephase obtained previously, washed with 240 mL of water, and then thesolvent was distilled off to obtain a crude product (63. 0 g) of theacetylene compound of formula (3) being a desired product. The crudeproduct was purified with silica gel column chromatography to obtain 44.0 g (yield 90%) of the desired product as yellow oily product.

¹H-NMR (CDCl₃) ppm: 8. 18(2H, d, J=9. 2 Hz), 7. 30(2H, d, J=9. 2 Hz), 2.68(1 H, s), 1. 73(6H, s)

EXAMPLE 2

To a 2 L-reaction flask equipped with a thermometer, a stirrer and adropping funnel, 283 g of N,N-dimethylacetamide (DMAc) was added, theresulting mixture was cooled to −13 to −12° C. and 34. 3 g (856 mmol) of60% sodium hydride (suspension in mineral oil) was added thereto. Then,74. 5 g (886 mmol) of 2-methyl-3-butyn-2-ol was added dropwise toproduce an alkoxide (internal temperature: −10 to −8° C. , dropwiseaddition time: 3. 5 hours).

After stirring for 1. 5 hour, 100 g (709 mmol) of 4-nitrofluorobenzenewas added dropwise (internal temperature: −10 to −5° C. , dropwiseaddition time: 1. 5 hour), and after completion of dropwise addition theresulting mixture was stirred at the same temperature for 38 hours.Under the condition below 10° C. , 1420 mL of water was added to thereaction mixture, after stirring for 1 hour, 1420 g of ethyl acetate wasadded thereto and shaken and the resulting mixture was allowed to stand,separated into two-phase and the ethyl acetate phase was taken out. Theaqueous phase was extracted with 709 g of ethyl acetate and theresulting ethyl acetate phase was combined with the ethyl acetate phaseobtained previously, washed with 709 g of water, and then the solventwas distilled off to obtain a crude product (177 g) of the acetylenecompound of formula (3) being a desired product.

HPLC relative area percentages of acetylene compound of formula (3) andthe by-product of formula (4) after reaction for 38 hours and of thecrude products are shown in Table 1. TABLE 1 (3) (4) 38 hours-reaction95.0% 0.5% Crude product of (3) 93.8% 0.5%

REFERENTIAL EXAMPLE 1

To a 1 L-reaction flask equipped with a thermometer, a stirrer, Dimrothcondenser and a dropping funnel, 162 g of o-dichlrobenzene was added,heated to 170° C. , and the total amount of the crude product of theacetylene compound of formula (3) obtained in Example 2 dissolved in 186g of o-dichlorobenzene was added dropwise over 3 hours and 40 minutesthereto (internal temperature: 168 to 176° C. ). After completion ofdropwise addition the resulting mixture was stirred at the sametemperature for 1 hour and the solvent was distilled off to obtain 169 gof a crude product of 2,2-dimethyl-6-nitro-2H-1-benzopyran being adesired product. The crude product was dissolved in a mixed solvent of317 g of methanol and 56 g of water by heating, and gradually cooled to2° C. , and then was subjected to crystallization for 2 hours and 30minutes at 0 to 5° C. The resulting crystal was taken by filtration andwashed, then dried under a reduced pressure at 50° C. to obtain 137 g(yield: 94%) of 2,2-dimethyl-6-nitro-2H-1-benzopyran. As the crystal wascontaminated by mineral oil of sodium hydride and the like, it wassubjected to an internal standard determination, and had a purity of 89.4%. Consequently, the yield was 84% in the aggregate of 2 steps. Thevalues of physical property of the sample obtained by purifying withsilica gel column chromatography were as follows.

MP: 74. 6 to 74. 7° C. ¹H-NMR (CDCl₃) ppm: 8. 02(1 H, dd, J=8. 9, 2. 8Hz), 7. 89(1 H, d, J=2. 8 Hz), 6. 81(1 H, d, J=8. 9 Hz), 6. 36 (1H, d,J=9. 9 Hz), 5. 75 (1H, d, J=9. 9 Hz), 1. 48 (6H, s)

EXAMPLES 3 TO 5 Effect of Reaction Temperature and Amount of Solvent

Except that the reaction temperature and the amount of solvent werealtered, the reaction was carried out under the similar condition tothat of Example 2. HPLC relative area percentages of acetylene compoundof formula (3) and the by-product of formula (4) after the conclusion ofthe reaction and of the crude products are shown in Table 2.

In the meanwhile, the reaction time was altered depending on thereaction condition.

Further, the amount of solvent was shown in mass times based on the usedamount of 4-nitrofluorobenzene of formula (1).

For comparison, the results of Example 2 were also shown. TABLE 2Proportion after Proportion of Example Amount of solvent TemperatureTime reaction (%) of crude products No. (mass times) (° C.) (hr) (3) (4)(3) (4) 2 2.83 −10 to −5 38 95.0 0.5 93.8 0.5 3 2.84 −15 to −10 90 96.80.3 97.1 0.3 4 1.85 −10 to −3 41 93.2 0.8 93.1 0.8 5 3.85 −10 to −2 1792.8 0.7 94.2 0.5

EXAMPLE 6 Example in which N,N′-dimethylimidazolidinone (DMI) was usedas a solvent

To a 300 mL-reaction flask equipped with a thermometer, a stirrer and adropping funnel, 96. 0 g of N,N′-dimethylimidazolidinone (DMI) and 11. 6g (290 mmol) of 60% sodium hydride (suspension in mineral oil) wereadded, and 25. 2 g (300 mmol) of 2-methyl-3-butyn-2-ol was addeddropwise with stirring under cooling with ice to produce an alkoxide(internal temperature: 10° C. or less, dropwise addition time: 1. 5hour, stirring for 30 minute after dropwise addition).

Then, 33. 8 g (240 mmol) of 4-nitrofluorobenzene was added dropwise, andthe resulting mixture was reacted with stirring for 18 hours undercooling with ice. To the reaction mixture, 480 mL of toluene and 480 mLof water were added and the resulting mixture was shaken. After allowingto stand, the mixture was separated into two-phase and the toluene phasewas taken out. The aqueous phase was extracted with 240 mL of tolueneand the resulting toluene phase was combined with the toluene phaseobtained previously. The combined toluene phase was dried over anhydroussodium sulfate and filtered, and then the solvent was distilled off toobtain a crude product of the acetylene compound of formula (3) being andesired product. The crude product was subjected to silica gel columnchromatography (500 g of silica gel, elution solution: ethylacetate-hexane=1/20) to obtain 43. 5 g (yield 89%) a purified product ofthe acetylene compound of formula (3) as yellow oily product. HPLCanalysis showed that the relative area percentage of the desired productwas 91. 2% and the relative area percentage of 4-nitrofluorobenzene was7. 9%. As 4-nitrofluorobenzene showed a sensitivity ratio of 4 times,the corrected HPLC purity thereof was 97. 9%.

COMPARATIVE EXAMPLE 1

To a 1 L-reaction flask equipped with a thermometer, a stirrer and adropping funnel, 96 g of N,N-dimethylacetamide (DMAc) was added, theresulting mixture was cooled to 3° C. and 11. 6 g (289 mmol) of 60%sodium hydride (suspension in mineral oil) was added thereto. Then, 25.2 g (299 mmol) of 2-methyl-3-butyn-2-ol was added dropwise to produce analkoxide (internal temperature: 3 to 10° C. , dropwise addition time: 1hour).

Then, 33. 8 g (239 mmol) of 4-nitrofluorobenzene was added dropwise(internal temperature: 2 to 5° C. , dropwise addition time: 1. 5 hour),and after completion of dropwise addition the resulting mixture wasstirred at 10 to 15° C. for 20 hours. Thereafter, similarly to theprocedure of Example 2, a crude product of the acetylene compound offormula (3) was obtained.

HPLC relative area percentages of acetylene compound of formula (3) andthe by-product of formula (4) after reaction for 18 hours and of thecrude product are shown in Table 3. TABLE 3 (3) (4) 18 hours-reaction72.2% 1.2% Crude product of (3) 83.1% 1.5%

COMPARATIVE EXAMPLE 2 Reaction between 4-nitrophenol and2-methyl-3-butyn-2-chloride

To a 3 L-reaction flask equipped with a thermometer and a stirrer, 148 g(1. 06 mol) of nitrophenol and 1000 mL of water were added, sodiumhydroxide aqueous solution [NaOH 64. 7 g (1. 62 mol)/H₂O 100 mL] wasadded and dissolved thereto (temperature was raised to 35° C. due toexothermic reaction). Then, 1100 mL of dichloromethane, 166 9 (1. 62mol) of 2-methyl-3-butyn-2-chloride and 92. 0 g of trimethylbenzylammonium hydroxide (40% methanol solution) were added successively, andthe resulting mixture was stirred at room temperature for 5 days. Thestirred solution was allowed to stand, separated into two-phase and thedichloromethane phase was taken out. The aqueous phase was extractedwith 500 mL of chloroform and the resulting chloroform phase wascombined with the dichloromethane phase obtained previously. Thecombined phase was washed with 1000 g of 10% sodium hydroxide aqueoussolution, 700 mL of water and 500 mL of water, successively, and thendried over anhydrous sodium sulfate. The resulting solution wassubjected to filtration and then the solvent distillation to obtain 71.3 g (yield 33%) of the acetylene compound of formula (3) being a desiredproduct as black brown oily product.

The present invention can establish a process for producing theacetylene compound of formula (3) that is useful as an intermediate ofpharmaceuticals, from 4-nitrofluorobenzene that is inexpensivelyavailable, in industrially and economically advantageous manner.

INDUSTRIAL APPLICABILITY

The acetylene compound of formula (3) produced according to the methodof the present invention is useful as for example an intermediate forsynthesizing an antifibrillatory agent or a hypotensive agent, andtherefore it is beneficial in pharmaceutical industry and the like.

1. A method for producing an acetylene compound of formula (3)

characterized by reacting 4-nitrofluorobenzene of formula (1)

with an alkoxide of 2-methyl-3-butyn-2-ol of formula (2)

at −20 to 10° C.
 2. The method for producing an acetylene compoundaccording to claim 1, wherein an amide type solvent is used as asolvent.
 3. The method for producing an acetylene compound according toclaim 1, wherein used amount of the solvent is 2 mass times or more thatof 4-nitrofluorobenzene.
 4. The method for producing an acetylenecompound according to claim 2, wherein used amount of the solvent is 2mass times or more that of 4-nitrofluorobenzene.